Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Research Center for Depression, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China; Key Laboratory for Drug Target Research and Pharmacodynamic Evaluation of Hubei Province, Wuhan, People's Republic of China.
Biol Psychiatry. 2021 Mar 15;89(6):615-626. doi: 10.1016/j.biopsych.2020.09.003. Epub 2020 Sep 10.
Deficiency in neuronal structural plasticity is involved in the development of major depressive disorder. TWIST1, a helix-loop-helix transcription factor that is essential for morphogenesis and organogenesis, is normally expressed at low levels in mature neurons. However, it is poorly understood what role TWIST1 plays in the brain and whether it is involved in the pathophysiology of depression.
Depressive-like behaviors in C57BL/6J mice were developed by chronic social defeat stress. Genetic and pharmacological approaches were used to investigate the role of the TWIST1-miR-214-PPAR-δ signaling pathway in depressive-like behaviors. Molecular biological and morphological studies were performed to define the molecular mechanisms downstream of TWIST1.
The expression of TWIST1 was positively correlated with depressive behaviors in humans and mice. Chronic stress elevated TWIST1 expression in the medial prefrontal cortex of mice, which was reversed by fluoxetine treatment. While the overexpression of TWIST1 increased susceptibility to stress, the knockdown of TWIST1 prevented the defective morphogenesis of dendrites of pyramidal neurons in layer II/III of the medial prefrontal cortex and alleviated depressive-like behaviors. Mechanistically, this prodepressant property of TWIST1 was mediated, at least in part, through the repression of miR-214-PPAR-δ signaling and mitochondrial function, which was also mimicked by genetic and pharmacological inhibition of PPAR-δ.
These results suggest that TWIST1 in the medial prefrontal cortex mediates chronic stress-induced dendritic remodeling and facilitates the occurrence of depressive-like behavior, providing new information for developing drug targets for depression therapy.
神经元结构可塑性不足与重度抑郁症的发展有关。TWIST1 是一种螺旋-环-螺旋转录因子，对于形态发生和器官发生至关重要，在成熟神经元中通常低表达。然而，TWIST1 在大脑中的作用以及它是否参与抑郁症的病理生理学尚不清楚。
通过慢性社交挫败应激在 C57BL/6J 小鼠中建立抑郁样行为。采用遗传和药理学方法研究 TWIST1-miR-214-PPAR-δ 信号通路在抑郁样行为中的作用。进行分子生物学和形态学研究以确定 TWIST1 的下游分子机制。
TWIST1 的表达与人及小鼠的抑郁行为呈正相关。慢性应激可使小鼠前额叶皮质中间部 TWIST1 的表达升高，氟西汀治疗可逆转这一现象。TWIST1 的过表达会增加对压力的易感性，而 TWIST1 的敲低可防止前额叶皮质中间部 II/III 层锥体神经元树突的形态发生缺陷，并缓解抑郁样行为。从机制上讲，TWIST1 的这种促抑郁作用至少部分是通过抑制 miR-214-PPAR-δ 信号和线粒体功能来介导的，这一作用也可通过遗传和药理学抑制 PPAR-δ 来模拟。
这些结果表明，前额叶皮质中间部的 TWIST1 介导了慢性应激诱导的树突重塑，并促进了抑郁样行为的发生，为开发抑郁症治疗的药物靶点提供了新信息。
